Micro-Surface and -Interfacial Tensions Measured Using the Micropipette Technique: Applications in Ultrasound-Microbubbles, Oil-Recovery, Lung-Surfactants, Nanoprecipitation, and Microfluidics

This review presents a series of measurements of the surface and interfacial tensions we have been able to make using the micropipette technique. These include: equilibrium tensions at the air-water surface and oil-water interface, as well as equilibrium and dynamic adsorption of water-soluble surfactants and water-insoluble and lipids. At its essence, the micropipette technique is one of capillary-action, glass-wetting, and applied pressure. A micropipette, as a parallel or tapered shaft, is mounted horizontally in a microchamber and viewed in an inverted microscope. When filled with air or oil, and inserted into an aqueous-filled chamber, the position of the surface or interface meniscus is controlled by applied micropipette pressure. The position and hence radius of curvature of the meniscus can be moved in a controlled fashion from dimensions associated with the capillary tip (~5–10 μm), to back down the micropipette that can taper out to 450 μm. All measurements are therefore actually made at the microscale. Following the Young–Laplace equation and geometry of the capillary, the surface or interfacial tension value is simply obtained from the radius of the meniscus in the tapered pipette and the applied pressure to keep it there. Motivated by Franklin’s early experiments that demonstrated molecularity and monolayer formation, we also give a brief potted-historical perspective that includes fundamental surfactancy driven by margarine, the first use of a micropipette to circuitously measure bilayer membrane tensions and free energies of formation, and its basis for revolutionising the study and applications of membrane ion-channels in Droplet Interface Bilayers. Finally, we give five examples of where our measurements have had an impact on applications in micro-surfaces and microfluidics, including gas microbubbles for ultrasound contrast; interfacial tensions for micro-oil droplets in oil recovery; surface tensions and tensions-in-the surface for natural and synthetic lung surfactants; interfacial tension in nanoprecipitation; and micro-surface tensions in microfluidics

From Single Microparticles to Microfluidic Emulsification: Fundamental Properties (Solubility, Density, Phase Separation) from Micropipette Manipulation of Solvent, Drug and Polymer Microspheres

The micropipette manipulation technique is capable of making fundamental single particle measurements and analyses. This information is critical for establishing processing parameters in systems such as microfluidics and homogenization. To demonstrate what can be achieved at the single particle level, the micropipette technique was used to form and characterize the encapsulation of Ibuprofen (Ibp) into poly(lactic-co-glycolic acid) (PLGA) microspheres from dichloromethane (DCM) solutions, measuring the loading capacity and solubility limits of Ibp in typical PLGA microspheres. Formed in phosphate buffered saline (PBS), pH 7.4, Ibp/PLGA/DCM microdroplets were uniformly solidified into Ibp/PLGA microparticles up to drug loadings (DL) of 41%. However, at DL 50 wt% and above, microparticles showed a phase separated pattern. Working with single microparticles, we also estimated the dissolution time of pure Ibp microspheres in the buffer or in detergent micelle solutions, as a function of the microsphere size and compare that to calculated dissolution times using the Epstein-Plesset (EP) model. Single, pure Ibp microparticles precipitated as liquid phase microdroplets that then gradually dissolved into the surrounding PBS medium. Analyzing the dissolution profiles of Ibp over time, a diffusion coefficient of 5.5 ± 0.2 × 10−6 cm2/s was obtained by using the EP model, which was in excellent agreement with the literature. Finally, solubilization of Ibp into sodium dodecyl sulfate (SDS) micelles was directly visualized microscopically for the first time by the micropipette technique, showing that such micellization could increase the solubility of Ibp from 4 to 80 mM at 100 mM SDS. We also introduce a particular microfluidic device that has recently been used to make PLGA microspheres, showing the importance of optimizing the flow parameters. Using this device, perfectly smooth and size-homogeneous microparticles were formed for flow rates of 0.167 mL/h for the dispersed phase (Qd) and 1.67 mL/h for the water phase (Qc), i.e., a flow rate ratio Qd/Qc of 10, based on parameters such as interfacial tension, dissolution rates and final concentrations. Thus, using the micropipette technique to observe the formation, and quantify solvent dissolution, solidification or precipitation of an active pharmaceutical ingredient (API) or excipient for single and individual microparticles, represents a very useful tool for understanding microsphere-processes and hence can help to establish process conditions without resorting to expensive and material-consuming bulk particle runs

Manipulating Single Microdroplets of NaCl Solutions: Solvent Dissolution, Microcrystallization, and Crystal Morphology

A new “three-micropipette manipulation technique” for forming, dehydrating, crystallizing, and resolvating nanograms of salt material has been developed to study supersaturated single microdroplets and microcrystals. This is the first report of studies that have measured in situ both supersaturation (as homogeneous nucleation) and saturation (as microcrystal redissolution) for single microdroplets of NaCl solution using the micropipette technique. This work reports a measure of the critical supersaturation concentration for homogeneous nucleation of NaCl (10.3 ± 0.3 M) at a supersaturation fraction of <i>S</i> = 1.9, the saturation concentration of NaCl in aqueous solution as measured with nanograms of material (5.5 ± 0.1 M), the diffusion coefficient for water in octanol, <i>D</i> = (1.96 ± 0.10) × 10^–6 cm²/s, and the effect of the solvent’s activity on dissolution kinetics. It is further shown that the same Epstein–Plesset (EP) model, which was originally developed for diffusion-controlled dissolution and uptake of gas, and successfully applied to liquid-in-liquid dissolution, can now also be applied to describe the diffusion-controlled uptake of water from a water-saturated environment using the extended activity-based model of Bitterfield et al. This aspect of the EP model has not previously been tested using single microdroplets. Finally, it is also reported how the water dissolution rate, rate of NaCl concentration change, resulting crystal structure, and the time frame of initial crystal growth are affected by changing the bathing medium from octanol to decane. A much slower loss of water-solvent and concomitant slower up-concentration of the NaCl solute resulted in a lower tendency to nucleate and slower crystal growth because much less excess material was available at the onset of nucleation in the decane system as compared to the octanol system. Thus, the crystal structure is reported to be dendritic for NaCl solution microdroplets dissolving rapidly and nucleating violently in octanol, while they are formed as single cubic crystals in a gentler way for solution-dissolution in decane. These new techniques and analyses can now also be used for any other system where all relevant parameters are known. An example of this is control of drug/hydrogel/emulsion particle size change due to solvent uptake